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Coming dissertations at MedFak

  • On Surgical Treatment of Aortic Pathology Author: Jacob Budtz-Lilly Link: Publication date: 2019-11-26 07:07

    The use of endovascular aneurysm repair (EVAR) in the treatment of abdominal aortic aneurysms has advanced from a premature characterization as a “failed experiment” in early 2000 to the predominant modern method of treatment. Technology has accommodated initial shortcomings, but it has also led to expansions in the treatment of ruptured aneurysms and complex aortic pathologies. The overall aim of this thesis is to characterize the contemporary utilization of endovascular repair in the international setting and to evaluate its expanding use in complex aortic disease treatment.

    Paper I is an analysis of outcomes after intact aneurysm treatment from registries of 12 countries. From 2005 to 2013, and with 83,253 patients included, it was shown that the use of EVAR has increased while, the perioperative mortality has decreased. This was counterbalanced by a worsening mortality for those patients treated with open aortic repair.

    Paper II is an analysis of ruptured aneurysms from the above-mentioned international registries. EVAR is also increasing for these patients, although open repair is still the predominant treatment strategy in most centres. Perioperative mortality was superior for EVAR patients, despite increased age and comorbidities. An association between patient-volume and perioperative mortality could be shown for open repair, but the same could not be demonstrated for EVAR.

    Paper III is an evaluation of the adaptation of a total endovascular approach for the treatment of complex abdominal aortic aneurysms from a single centre. The technical success and midterm mortality, as well as post-operative complications, including spinal ischemia, were similar to those reported from large and multi-centre analyses. Previous studies reveal disparate results for centres performing open complex aortic repair. The results here suggest that a total endovascular approach is feasible for dedicated centres contemplating this strategy.  

    Paper IV is an analysis of multiple pre-, peri-, and post-operative variables documented from complex aneurysm procedures. A relationship between increased complexity and variables such as anaesthesia duration, bleeding, hospital stay, and radiation exposure was found. As patients and their comorbidities increase, a decision to embark on a complex procedure should be made with due diligence to these relationships.

    Paper V is a technical analysis of patients following acute treatment for Type A aortic dissections. Many patients are unfit for open aortic arch repair. Based on current availability of endovascular aortic stentgrafts, it was shown that the majority of patients can be treated endovascularly, while anticipated device improvements should further increase the proportion of eligibility. 

  • Mechanisms in Tendon Healing : Pain, Biomarkers and the Role of Mast Cells Author: Abdul Alim Link: Publication date: 2019-11-22 10:09

    Tendon injuries and tendinopathy are common disorders, but the underlying mechanisms are not well understood. The overall aim of this thesis was to better understand the mechanisms underlying tendon healing, pain, and inflammation.

    The aim of the first study was to assess biomarkers of tendon healing, including procollagen type I (PINP) and type III (PIIINP) in relation to patient outcome in 65 patients with Achilles tendon rupture (ATR). At two weeks post-ATR, PINP and PIIINP-levels were quantified using microdialysis followed by ELISA. At one-year post-ATR patient outcome was assessed using the validated Achilles tendon Total Rupture Score. We found that higher ratio of PINP and PIIINP to total protein were significantly associated with less pain but more fatigue in the affected limb.

    In the second study, we applied Intermittent Pneumatic Compression (IPC) therapy for two weeks to stimulate tendon healing. The patients received either adjuvant IPC treatment or treatment-as-usual in a plaster cast without IPC. We observed that IPC therapy significantly increased PINP levels in the injured tendon, suggesting enhanced healing response.

    In our third study, we investigated healing response and the role of mast cells (MCs) in-vivo using an ATR rat model. Three weeks postoperatively, we demonstrated an increased number of MCs and a higher proportion of degranulated MCs in the injured tendon compared to the control. We further established that MCs in the injured tendon were positive for the glutamate receptor NMDAR1.

    In our final study, we assessed the effect of glutamate stimulation on in-vitro-derived mouse bone marrow MCs. Mast cell degranulation was quantified through β-hexosaminidase release, immunofluorescence was used to quantify NMDARs at the protein level, and RT-qPCR/microarray was used to study the expression of NMDARs and associated genes. Glutamate induced a robust upregulation of glutamate receptors of both ionotropic and metabotropic type, both at the mRNA and at protein level. NMDAR1 co-localized with glutamate in the membrane of MCs, thereby confirming an interaction between glutamate and its receptor. Glutamate also induced expression of pro-inflammatory compounds such as IL-6 and CCL2 and transcription factors such as Egr2, Egr3 and FosB. Moreover, the NMDA-channel blocker MK-801 completely abrogated the response of MCs to glutamate, supporting a functional glutamate–glutamate receptor axis in MCs.

    Together, findings presented in this dissertation reveal possible mechanisms of tendon healing in relation to pain and function, and establish a novel principle for how immune cells can communicate with nerve cells after ATR.

  • Regional Lung Mechanics and Influence of an Active Diaphragm in Experimental Lung Injury Author: Mariangela Pellegrini Link: Publication date: 2019-11-22 08:05

    Despite being an essential life-support strategy in severe respiratory failure, mechanical ventilation can, if not optimally set and monitored, lead to injury of the lung parenchyma and diaphragm. These conditions are called ventilator-induced lung injury and ventilator-induced diaphragmatic dysfunction (VIDD), respectively. Although substantial progress has been made in the ventilator management of severely lung-injured patients, we are still far from a fully protective mechanical ventilation. In consideration of this gap of knowledge, this doctoral thesis aimed at investigating regional lung mechanics during both inspiration and expiration, in both controlled and assisted ventilation. Particular emphasis was placed on the expiratory phase, which is involved in expiratory flow limitation, airway closure and atelectasis formation, although commonly considered non-harmful.

    A novel methodological approach has been the fundamental basis for this research project. The combination of respiratory mechanics, diaphragmatic electromyographic activity and lung imaging enabled a breath-by-breath analysis at high temporal and spatial resolution.

    In Study I, the gravitational field affected the distribution of gas and transpulmonary pressures, as previously shown. This effect differed between healthy and injured lungs. Moreover, lung injury induced a heterogeneous distribution of gas within the lungs, as well as an increased gravitational gradient in transpulmonary pressure. Study I was mainly aimed at testing the new methodological approach centred on the investigation of regional lung mechanics.

    In Study II, the focus was on assisted ventilation and the phenomenon of gas redistribution within the lungs. Large pendelluft events had been demonstrated in disproportionate inspiratory efforts. In Study II, we showed that large pendelluft resulting from pathological respiratory drive could be attenuated by high positive end expiratory pressure (PEEP). Moreover, we showed that transient and widespread small gas redistribution events occur at all times during inspiration. Assisted ventilation and high PEEP reduced the size of gas redistribution as compared with controlled ventilation and low PEEP.

    In Study III, we demonstrated a diaphragmatic expiratory contraction in lungs prone to collapse, serving to brake the expiratory flow. It preserved end expiratory lung volume (EELV) and counteracted tidal atelectasis. However, the expiratory brake induced by diaphragmatic contraction is a known cause of VIDD.

    In Study IV, we tested the effects of external expiratory resistances (ExpR). We showed that, by applying ExpR, an expiratory brake was induced. The beneficial effects on EELV were retained, while the diaphragm could quickly relax during the expiration, thus reducing the risk of VIDD.